Anales RANF

S13-02 ATP IN ASTROGLIAL CONTROL OF SYNAPTIC PLASTICITY IN AGEING AND AD Ulyana Lalo 1 , Alexander Bogdanov 2 and Yuriy Pankratov 1,2 1- School of Life Sciences, University of Warwick, Gibbet Hill Campus, Coventry CV4 7AL, UK; 2- Immanuel Kant Baltic Federal University, 2 Universitetskaya str., Kaliningrad, Russia ; Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. Still, the mechanisms of gliotransmission remain uncertain with SNARE-dependent exocytosis being the most intriguing and debated pathway. Previously, we showed that SNARE-dependent exocytosis of ATP from neocortical and hippocampal astrocytes can be triggered by Ca 2+ -elevation via direct UV-uncaging or via glia- specific receptors (PAR-1, CB1 or α 1-adrenoceptors). We also showed that activation of astrocytes initiated a burst of ATP receptor-mediated currents in adjacent pyramidal neurons. These purinergic currents can be inhibited by intracellular perfusion of astrocytes with Tetanus Toxin light chain (TeNTx), or by astroglia-specific expression of dn-SNARE protein, verifying their origin via astroglial exocytosis. We found out that astrocyte-derived ATP can down-regulate phasic and tonic GABAergic currents, acting via Ca 2+ -permeable P2X receptors on pyramidal neurons. Also, P2X receptors activated by astrocyte-derived ATP can facilitate trafficking of AMPA receptor into synapse. Hence, astroglia-derived ATP can strongly influence the balance between excitation and inhibition in neural networks and facilitate the long- term synaptic plasticity. Our data show that synergetic action of astrocyte-derived ATP and D-serine is essential for synaptic plasticity. The LTP was impaired in the neocortex of dn-SNARE mice but could be rescued by application of exogenous or non-hydrolysable ATP analogs. We also have found out that weak sub-threshold theta-burst stimulation can induce LTP when astrocytes are additionally activated via endocannabinoid or noradrenaline receptors. This facilitation is dependent on the activation of neuronal ATP receptors and can be significantly reduced by perfusion of astrocytes with TeNTx. Moreover, we have found out the deficit in working memory of dn-SNARE mice; this is a first evidence of physiological relevance of glial exocytosis of ATP in vivo. There is growing evidence that impairment of glial function can be related to the pathogenesis of many neurological disorders. We observed the considerable decrease in the astrocytic Ca 2+ -signaling and release of ATP in the aged wild-type and Alzheimer’s disease model mice. Impairment of glia-derived regulation altered the balance between excitation and inhibition leading to age- and AD-related deficit in the synaptic plasticity. Importantly, environmental enrichment (EE) or caloric restriction enhanced astroglial Ca 2+ -signalling and Ca 2+ -dependent release of ATP thereby ameliorating the age-related decline in purinergic glia-derived modulation of synaptic plasticity. Combined, our data strongly support the importance of glia-derived ATP for astrocyte- neuron communication and show that age-related decline in gliotransmitter release can bring significant contribution to pathogenesis of neurodegenerative diseases.